This Revision Application proposal seeks to break new ground in regard to the scope and aims of the parent RO1, which was awarded for 5 years beginning 03/01/08. Consistent with the goals of the Recovery Act and notice NOT-OD-09- 058, we plan to systematically collect and analyze olfactory epithelial biopsy tissue as well as perform detailed peripheral and central electrophysiological studies of the olfactory system in schizophrenia patients and healthy controls. Olfactory epithelium is unique in that it constitutes the sole source of regenerating neural cells that can be obtained from a living human. That is, the location of olfactory receptor neurons in the nasal epithelium allows noninvasive access to these neurons in living subjects. This offers a unique opportunity to directly assess neuronal integrity in vivo in patients. Primary cultures derived from human olfactory epithelial biopsies can subsequently be utilized to study neurobiological characteristics of individuals under different conditions and disease states. The collection of olfactory biopsy tissue will allow for further characterization of basal cells in OE in terms of their ultrastructural features as well as gene expression profiling to better define the role of each cell type in neurogenesis. New methodologies will be employed to examine peripheral components of olfactory sensory processing, i.e., olfactory event-related potentials (OERPs), as well as more traditional scalp recordings of the olfactory- evoked potential. We will study 30 schizophrenia patients and 30 unrelated healthy controls. Results from the in vivo electrophysiological studies will be integrated with the results of the cellular and molecular studies that use ORN tissue biopsies obtained from the same subjects. Our working model is that olfactory deficits reflect genetically-mediated abnormalities in neuron-to-neuron connectivity, arising from neurodevelopmentally disturbed processes of neurogenesis and synapse formation. Penn Medicine contributes substantially to the local economy. In 2008, Penn Medicine created 37,000 jobs and $5.4 billion in regional economic activity, with the area's highly trained workforce producing more than 24,600 applications for just 840 open Penn staff research positions. The current proposal will create or retain 2.5 jobs. PUBLIC HEALTH RELEVANCE: Schizophrenia is currently thought to be a complex genetic disorder, with altered neuronal development, perhaps very early in life, important in determining vulnerability. Neurogenesis and neurodevelopment occur in the adult olfactory epithelium (OE), and the collection and study of olfactory biopsy tissue may provide insights into the neuro- biological basis of altered neurodevelopment in this disorder. We plan to collect and analyze OE biopsy tissue as well as perform detailed peripheral and central electrophysiological studies of the olfactory system in schizophrenia patients and healthy controls. Penn Medicine contributes substantially to the local economy. In 2008, Penn Medicine created 37,000 jobs and $5.4 billion in regional economic activity, with the area's highly trained workforce producing more than 24,600 applications for just 840 open Penn staff research positions. The current proposal will create or retain 2.5 jobs.